药学学报, 2019, 54(11): 1888-1894
引用本文:
刘昕彦, 邵瑞, 贺爽, 朱彦. 类器官和立体细胞模型在中药心脏毒性评价中的应用前景[J]. 药学学报, 2019, 54(11): 1888-1894.
LIU Xin-yan, SHAO Rui, HE Shuang, ZHU Yan. Application prospect of organoids and 3D-cell models in evaluation of cardiotoxicity of traditional Chinese medicine[J]. Acta Pharmaceutica Sinica, 2019, 54(11): 1888-1894.

类器官和立体细胞模型在中药心脏毒性评价中的应用前景
刘昕彦1,2, 邵瑞1,2, 贺爽1,2, 朱彦1,2
1. 天津中医药大学, 天津市现代中药重点实验室, 天津 300193;
2. 天津国际生物医药联合研究院中药新药研发中心, 天津 300457
摘要:
心脏毒性是导致药物研发失败和上市后撤市的原因之一。然而,目前的药物心脏毒性评价方法存在临床相关性低、重现性低、处理量小等缺点。建立准确可靠的方法评价药物的心脏毒性是当前药物安全性评价及毒理学研究亟需解决的问题。心脏类器官作为新一代的药物心脏毒性评价模型,极大程度保留了心脏细胞在体内的生物特性和功能,更加真实、准确地反映药物对心脏的影响。本文就心脏立体细胞模型和类器官体外培养技术的进展作一综述,并重点讨论心脏类器官在中药心脏毒性评价中的应用及其发展潜力。文章还讨论了细胞和类器官模型在面对中药心脏毒性评价独特挑战方面的优势和前景。
关键词:    中药      心脏毒性      二维细胞      三维细胞      类器官      毒性评价技术     
Application prospect of organoids and 3D-cell models in evaluation of cardiotoxicity of traditional Chinese medicine
LIU Xin-yan1,2, SHAO Rui1,2, HE Shuang1,2, ZHU Yan1,2
1. Tianjin Modern Chinese Medicine Key Laboratory, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China;
2. Tianjin International Biomedical Research Institute, Chinese Medicine New Drug Research and Development Center, Tianjin 300457, China
Abstract:
Cardiotoxicity is one of the main causes of failure in new drug development or drug withdrawal from the market. However, current methods for evaluation of drug cardiotoxicity suffer the shortcomings such as low clinical relevance, low reproducibility and lack of high throughput screening capacity. Therefore, there is an urgent need for establishing more accurate and reliable methods for cardiotoxicity evaluation of drugs. As a new generation of drug cardiotoxicity evaluation, cardiac organs in culture retain the biological characteristics and functions of heart cells in the body, and can realistically and accurately respond to the effects of drugs. This article reviews recent progress of in vitro culture of cardiac organs and 3D-cell models, with focuses on application and development potential of cardiac organs for evaluation of cardiotoxicity of traditional Chinese medicine. The advantage and future prospective of such cell- and organ-based models for unique challenges in evaluation of cardiotoxicity of traditional Chinese medicine have been discussed.
Key words:    traditional Chinese medicine    cardiotoxicity    two-dimensional cell    three-dimensional cell    organoid    toxicity evaluation technology   
收稿日期: 2019-02-14
DOI: 10.16438/j.0513-4870.2019-0105
基金项目: 国家重点研发计划项目(2018YFC1704500);国家科技重大专项(2018ZX01031301);国家自然科学基金资助项目(81873037).
相关功能
PDF(368KB) Free
打印本文
0
作者相关文章
刘昕彦  在本刊中的所有文章
邵瑞  在本刊中的所有文章
贺爽  在本刊中的所有文章
朱彦  在本刊中的所有文章

参考文献:
[1] Pereira GC, Silva AM, Diogo CV, et al. Drug-induced cardiac mitochondrial toxicity and protection: from doxorubicin to carvedilol[J]. Curr Pharm Des, 2011, 17: 2113-2129.
[2] Liang X, Li H, Li S. A novel network pharmacology approach to analyse traditional herbal formulae: the Liu-Wei-Di-Huang pill as a case study[J]. Mol Biosyst, 2014, 10: 1014-1022.
[3] Tan Y, Ko J, Liu X, et al. Serum metabolomics reveals betaine and phosphatidylcholine as potential biomarkers for the toxic responses of processed Aconitum carmichaelii Debx[J]. Mol Biosyst, 2014, 10: 2305-2316.
[4] Liang P, Lan F, Lee AS, et al. Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity[J]. Circulation, 2013, 127: 1677-1691.
[5] Wu Y, You J, Li F, et al. MicroRNA-542-3p suppresses tumor cell proliferation via targeting Smad2 inhuman osteosarcoma[J]. Oncol Lett, 2018, 15: 6895-6902.
[6] Li RZ. Adverse reactions and preventive measures of oral chinese medicine[J]. China Health Stand Manag (中国卫生标准管理), 2017, 8: 92-93.
[7] Gui C, Chen MH, Lin S, et al. Cytotoxicity effects of shikonin on rat cardiomyocytes in vitro[J]. Pharmacol Clin Chin Mater Med (中药药理与临床), 2010, 26: 33-36.
[8] Li H, Wang RJ, Ouyang F, et al. Influences of the Toad Venom on Bufo gargarizans heart activities[J]. J Jilin Norm Univ (Nat Sci Ed) (吉林师范大学学报(自然科学版)), 2014, 35: 142-144.
[9] Huang HL, Liu HG, Meng Y, et al. Effect of nitidine chloride on the heart development of zebrafish embryos[J]. Guangxi Med J (广西医学), 2011, 33: 546-548.
[10] Wang XC. Comparsion of the Arrhythmogenic Effects between ACO and MACO on Ventricular Myocytes of Guinea-pig and Their Underlying Cellular Mechanisms (乌头碱和新乌头碱致心律失常作用比较及其细胞学机制)[D]. Shijiazhuang: Hebei Medical University, 2013.
[11] Huang CC, Chen PC, Huang CW, et al. Aristolochic acid induces heart failure in zebrafish embryos that is mediated by inflammation[J]. Toxicol Sci, 2007, 100: 486-494.
[12] Wang SF, Liu KC, Wang XM, et al. Preliminary study on cardiotoxicity of celastrol to zebrafish embryo[J]. Chin Pharmacol Bull (中国药理学通报), 2009, 25: 634-636.
[13] Correia C, Koshkin A, Duarte P, et al. 3D aggregate culture improves metabolic maturation of human pluripotent stem cell derived cardiomyocytes[J]. Biotechnol Bioeng, 2018, 115: 630-644.
[14] Trac D, Maxwell JT, Brown ME, et al. Aggregation of child cardiac progenitor cells into spheres activates notch signaling and improves treatment of right ventricular heart failure[J]. Circ Res, 2019, 124: 526-538.
[15] Yue X, Acun A, Zorlutuna P. Transcriptome profiling of 3D co-cultured cardiomyocytes and endothelial cells under oxidative stress using a photocrosslinkable hydrogel system[J]. Acta Biomater, 2017. DOI: 10.1016/j.actbio.2017.06.031.
[16] Campbell M, Chabria M, Figtree GA, et al. Stem cell-derived cardiac spheroids as 3D in vitro models of the human heart microenvironment[J]. Methods Mol Biol, 2018. DOI: 10.1007/7651_2018_187.
[17] Varzideh F, Pahlavan S, Ansari H, et al. Human cardiomyocytes undergo enhanced maturation in embryonic stem cell-derived organoid transplants[J]. Biomaterials, 2019. DOI: 10.1016/j.biomaterials.2018.11.033.
[18] Smith E, Cochrane WJ. Cystic organoid teratoma: (report of a case)[J]. Can Med Assoc J, 1946, 55: 151-152.
[19] Weeber F, Ooft SN, Dijkstra KK, et al. Tumor organoids as a pre-clinical cancer model for drug discovery[J]. Cell Chem Biol, 2017, 24: 1092-1100.
[20] Cortina C, Turon G, Stork D, et al. A genome editing approach to study cancer stem cells in human tumors[J]. EMBO Mol Med, 2017, 9: 869-879.
[21] Briem E, Ingthorsson S, Traustadottir GA, et al. Application of the D492 cell lines to explore breast morphogenesis, EMT and cancer progression in 3D culture[J]. Mammary Gland Biol Neoplasia, 2019. DOI: 10.1007/s10911-018-09424-w.
[22] Kar S, Molla MS, Katti DR, et al. Tissue-engineered nanoclay-based 3D in vitro breast cancer model for studying breast cancer metastasis to bone[J]. J Tissue Eng Regen Med, 2019, 13: 119-130.
[23] Zhao H, Yan C, Hu Y, et al. Sphere‑forming assay vs organoid culture: determining long‑term stemness and the chemoresistant capacity of primary colorectal cancer cells[J]. Int J Oncol, 2019, 54: 893-904.
[24] Fontana F, Raimondi M, Marzagalli M, et al. Epithelial-to-mesenchymal transition markers and CD44 isoforms are differently expressed in 2D and 3D cell cultures of prostate cancer cells[J]. Cells, 2019. DOI: 10.3390/cells8020143.
[25] Haq S, Samuel V, Haxho F, et al. Sialylation facilitates self-assembly of 3D multicellular prostaspheres by using cyclo-RGDfK (TPP) peptide[J]. Onco Targets Ther, 2017, 10: 2427-2447.
[26] Guan Y, Xu D, Garfin PM, et al. Human hepatic organoids for the analysis of human genetic diseases[J]. JCI Insight, 2017, 2: 94954.
[27] Anabazhagan AN, Chatterjee I, Priyamvada S, et al. Methods to study epithelial transport protein function and expression in native intestine and caco-2 cells grown in 3D[J]. J Vis Exp, 2017. DOI: 10.3791/55304.
[28] Fernando EH, Dicay M, Stahl M, et al. A simple, cost-effective method for generating murine colonic 3D enteroids and 2D monolayers for studies of primary epithelial cell function[J]. Am J Physiol Gastrointest Liver Physiol, 2017, 313: G467-G475.
[29] Kaisar MA, Sajja RK, Prasad S, et al. New experimental models of the blood-brain barrier for CNS drug discovery[J]. Expert Opin Drug Discov, 2017, 12: 89-103.
[30] Pamies D, Barreras P, Block K, et al. A human brain microphysiological system derived from induced pluripotent stem cells to study neurological diseases and toxicity[J]. ALTEX, 2017, 34: 362-376.
[31] Fan L, Liu C, Chen X, et al. Directing induced pluripotent stem cell derived neural stem cell fate with a three-dimensional biomimetic hydrogel for spinal cord injury repair[J]. ACS Appl Mater Interfaces, 2018, 10: 17742-17755.
[32] Cai Y, Chen Y, Zhou WT, et al. Research advancement in the construction and applications of microfluidic devices for in vitro blood-brain barrier research[J]. Acta Pharm Sin (药学学报), 2019, 54: 269-280.
[33] Lemme M, Ulmer BM, Lemoine MD, et al. Atrial-like engineered heart tissue: an in vitro model of the human atrium[J]. Stem Cell Rep, 2018, 11: 1378-1390.
[34] Rogozhnikov D, O'Brien PJ, Elahipanah S, et al. Scaffold free bio-orthogonal assembly of 3-dimensional cardiac tissue via cell surface engineering[J]. Sci Rep, 2016, 6: 39806.
[35] Zhang YS, Arneri A, Bersini S, et al. Bioprinting 3D microfibrous scaffolds for engineering endothelialized myocardium and heart-on-a-chip[J]. Biomaterials, 2016. DOI: 10.1016/j.biomaterials.2016.09.003.
[36] Hoang P, Wang J, Conklin BR, et al. Generation of spatial-patterned early-developing cardiac organoids using human pluripotent stem cells[J]. Nat Protoc, 2018, 13: 723-737.
[37] Rogers AJ, Miller JM, Kannappan R, et al. Cardiac tissue chips (CTCs) for modelling cardiovascular disease[J]. IEEE Trans Biomed Eng, 2019. DOI: 10.1109/TBME.2019.2905763.
[38] Lee MO,Jung KB, Jo SJ, et al. Modelling cardiac fibrosis using three-dimensional cardiac microtissues derived from human embryonic stem cells[J]. J Biol Eng, 2019. DOI: 10.1186/s13036-019-0139-6.
[39] Yang H, Wei L, Liu C, et al. Engineering human ventricular heart tissue based on macroporous iron oxide scaffolds[J]. Acta Biomater, 2019. DOI: 10.1016/j.actbio.2019.02.024.
[40] Gao Y, Wang YP, Song G, et al. Progress in electrophysiological research of cardiomyocytes in traditional Chinese medicine[J]. Chin J Integr Med Cardio (中西医结合心脑血管病杂志), 2016, 14: 35-38.
[41] Cao XY, Zheng WY, Lu YB, et al. Advancement in ion channel research-automation patch clamp technology[J]. Mod Instrument (现代仪器), 2007, 13: 47-50.
[42] Chen XN, Zhu Y. Application potentials of hiPSC-derived cardiomyocytes in preclinical cardiotoxicity screening and post-marketing safety reevaluation of Chinese medicine[J]. Tianjin J Tradit Chin Med (天津中医药), 2017, 34: 76-81.
[43] Becker N, Stoelzle S, Göpel S, et al. Minimized cell usage for stem cell-derived and primary cells on an automated patch clamp system[J]. J Pharmacol Toxicol Methods, 2013, 68: 82-87.
[44] Stoelzle S, Haythornthwaite A, Kettenhofen R, et al. Automated patch clamp on m ESC-derived cardiomyocytes for cardiotoxicity prediction[J]. J Biomol Screen, 2011, 16: 910-916.
[45] Chen Z. Molecular Mechanism of Cardiotoxicity Induced by Tripterine (雷公藤红素致心脏毒性的分子机制研究)[D]. Nanjing: Nanjing Normal University, 2012.
[46] Wang T, Chen X, Yu J, et al. High-throughput electrophysiology screen revealed cardiotoxicity of strychnine by selectively targeting hERG channel[J]. Am J Chin Med, 2018, 46: 1825-1840.
[47] Scheel O, Frech S, Amuzescu B, et al. Action potential characterization of human induced pluripotent stem cell-derived cardiomyocytes using automated patch-clamp technology[J]. Assay Drug Dev Technol, 2014, 12: 457-469.
[48] Wu Q, Chubykin AA. Application of automated image-guided patch clamp for the study of neurons in brain slices[J]. J Vis Exp, 2017. DOI: 10.3791/56010.
[49] Zhu J, Wang M, Zhu Y. Quantitative cardiotoxicity assessment of gambogic acid using multiple cellular phenotype analysis[J]. Chin J Pharmacol Toxicol (中国药理学与毒理学杂志), 2017, 31: 73-79.
[50] Zhang Q. The Pharmacological Components and Mechanism of Salvia Miltiorrhiza Were Found Based on the Myocardial Injury Model Induced by Doxorubicin (基于多柔比星致心肌损伤模型发现丹参药效成分及作用机制)[D]. Beijing: Beijing University of Chinese Medicine, 2017.
[51] Ren SJ. Discovery of Cardiotoxicity Caused by Ophiopogon Saponins D' and Its Mechanism (麦冬皂苷D’ 致心脏毒性的发现及其机制研究)[D]. Nanning: Guangxi Medical University, 2018.
[52] Cui W, Li YL, Wu YN, et al. Application of high-content screening and flow cytometry analysis techniques to evaluation of myocardial fibroblasts proliferation[J]. Acta Physiol Sin (生理学报), 2014, 66: 215-222.
[53] Zhang MY, Yu YY, Wang SF, et al. Cardiotoxicity evaluation of nine alkaloids from Rhizoma Coptis[J]. Hum Exp Toxicol, 2018, 37: 185-195.
[54] Chen Z, Cen X, Yang J, et al. Synthesis of urea analogues bearing N-alkyl-N'-(thiophen-2-yl) scaffold and evaluation of their innate immune response to toll-like receptors[J]. Eur J Med Chem, 2019. DOI: 10.1016/j.ejmech.2019.02.067.
[55] Halaidych OV, Cochrane A, van den Hil FE, et al. Quantitative analysis of intracellular Ca2+ release and contraction in hiPSC-derived vascular smooth muscle cells[J]. Stem Cell Rep, 2019, 12: 647-656.
[56] Archer CR, Sargeant R, Basak J, et al. Characterization and validation of a human 3D cardiac microtissue for the assessment of changes in cardiac pathology[J]. Sci Rep, 2018, 8: 10160.
[57] Takeda M, Miyagawa S, Fukushima S, et al. Development of in vitro drug-induced cardiotoxicity assay by using three-dimensional cardiac tissues derived from human induced pluripotent stem cells[J]. Tissue Eng Part C Methods, 2018, 24: 56-67.
[58] Lu HF, Leong MF, Lim TC, et al. Engineering a functional three-dimensional human cardiac tissue model for drug toxicity screening[J]. Biofabrication, 2017, 9: 025011.
相关文献:
1.张钰浩, 颜才川, 王芳, 李宝馨, 杨宝峰.中药影响hERG钾通道致长-QT综合征机制的研究进展[J]. 药学学报, 2019,54(11): 1881-1887
2.李婷婷, 李瑞红, 刘振兴, 张乐, 王杰, 常乐, 陈志强, 施艳霞, 李朋彦, 李春雨, 刘建红, 柏兆方, 王伽伯, 王韫芳, 柳娟, 肖小河.基于类器官3D培养的何首乌易感物质肝毒性评价[J]. 药学学报, 2017,52(7): 1048-1054
3.李婷婷, 李瑞红, 刘振兴, 张乐, 王杰, 常乐, 陈志强, 施艳霞, 李朋彦, 李春雨, 刘建红, 柏兆方, 王伽伯, 王韫芳, 柳娟, 肖小河.基于类器官3D培养的何首乌易感物质肝毒性评价[J]. 药学学报,